Cortical excitation and inhibition following focal traumatic brain injury

Cortical compression can be a significant problem in many types of brain injuries, such as brain trauma, localized brain edema, hematoma, focal cerebral ischemia, or brain tumors. Mechanical and cellular alterations can result in global changes in excitation and inhibition on the neuronal network level even in the absence of histologically significant cell injury, often manifesting clinically as seizures. Despite the importance and prevalence of this problem, however, the precise electrophysiological effects of brain injury have not been well characterized. In this study, the changes in electrophysiology were characterized following sustained cortical compression using large-scale, multielectrode measurement of multiunit activity in primary somatosensory cortex in a sensory-evoked, in vivo animal model. Immediately following the initiation of injury at a distal site, there was a period of suppression of the evoked response in the rat somatosensory cortex, followed by hyper-excitability that was accompanied by an increase in the spatial extent of cortical activation. Paired-pulse tactile stimulation revealed a dramatic shift in the excitatory/inhibitory dynamics, suggesting a longer term hyperexcitability of the cortical circuit following the initial suppression that could be linked to the disruption of one or more inhibitory mechanisms of the thalamocortical circuit. Together, our results showed that the use of a sensory-evoked response provided a robust and repeatable functional marker of the evolution of the consequences of mild injury, serving as an important step toward in vivo quantification of alterations in excitation and inhibition in the cortex in the setting of traumatic brain injury.     

Reduced inhibition within primary motor cortex in patients with poststroke focal motor seizures

BACKGROUND: Following an ischemic brain lesion, the affected cortex undergoes structural and functional changes that may lead to increased cortical excitability or decreased inhibitory neuronal activity, resulting in the occurrence of poststroke epileptic seizures in 6 to 10% of patients with stroke. METHODS: To assess motor cortical excitability, transcranial magnetic stimulation (TMS) was used to determine the silent period (SP) duration in 84 consecutive patients with ischemic stroke. RESULTS: In a subpopulation of six patients (38 to 72 years old) a significant decrease of the SP duration (mean 116 +/- 14 msec) was detected in either the arm or the leg on the affected side as compared to the corresponding unaffected limb (mean 231 +/- 32 msec). This electrophysiologic abnormality was clinically associated with focal motor seizures in five of the six patients, whereas none of the other 76 patients with normal or prolonged SP durations developed seizures or epilepsy. CONCLUSIONS: Silent period shortening in this group reflects decreased inhibitory activity that may partly be related to functional or structural impairment of GABAergic interneurons. TMS may be of value for determining patients with stroke at risk for developing poststroke seizures.     

Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia.

Transcranial magnetic stimulation has been used in a double pulse paradigm to investigate the excitability of intrinsic motor cortical circuits in 15 patients with focal task specific dystonia of the right hand and a group of eight age matched controls. The left hemisphere was examined in five patients; in the remainder, both hemispheres were tested. There was no significant difference in stimulation threshold between patients and controls nor between the left and right hemispheres in the patients. There was a significant decrease in early corticocortical suppression when comparing stimulation of the left hemisphere in the patients and controls at interstimulus intervals of 1-15 ms (P < 0.01). There was no difference in the amount of suppression in the right and left hemispheres of the patients. It is concluded that in focal task specific dystonia there is shift in the balance between excitation and inhibition in local circuits of the motor cortex which leads to a net decrease in the amount of short latency suppression. These changes reflect disturbed basal ganglia input to the motor cortex. Reduced excitability of cortical inhibitory circuits may be one factor which contributes to the excessive and inappropriate muscle contraction which occurs during fine motor tasks in patients with focal dystonia.     

Selective focal inhibition of brain protein synthesis during generalized bicuculline seizures in newborn marmoset monkeys

Generalized epileptic seizures, induced in 5-7 day-old marmoset monkeys with bicuculline (5 mg/kg) produce striking focal disruption of protein synthesis. Inhibition of protein synthesis was most severe in the neocortex and hippocampus but was completely absent in the lateral geniculate nuclei and in the optic tract. In the cortex, regions in which protein synthesis was most severely reduced alternated with areas in which it was relatively preserved creating a columnar pattern. With few exceptions, subcortical gray matter structures in the forebrain and brainstem were less severely affected than the cortex. In the cerebellum, seizures appeared to have little effect on the proliferating external granular layer while the closely adjacent internal granular layer showed clear-cut inhibition. The focal nature of protein synthesis inhibition in brain during seizures suggests that the systemic effects of convulsions (e.g. hypoxemia, acidosis or changes in arterial blood pressure) are not a major factor. More likely, protein synthesis inhibition is related to the extent to which various cerebral structures participate in seizure activity.     

Ipsilateral forced head and eye turning at the end of the generalized tonic-clonic phase of versive seizures

We studied 61 spontaneous seizures in 27 epileptic patients with simultaneous EEG and video recording. Each seizure had an initial forced turning (versive) head and eye movement contralateral to the EEG location of seizure onset. Twelve of the 27 secondarily generalized versive seizures also had ipsilateral head and eye version at the end of the generalized convulsion. Initial contraversion and late ipsiversion both appeared to result from ictal activation of frontal contraversive areas in the hemisphere that, at the time, was predominantly involved in the seizure discharge. During initial contraversion, ictal activation was predominant in the hemisphere of seizure onset; during late ipsiversion, in the hemisphere involved by secondary generalization. Late version, unlike initial version, is frequently ipsilateral and cannot be assumed to indicate seizure onset in the contralateral hemisphere.     

Day/night patterns of focal seizures

PURPOSE: In many patients with epilepsy seizures occur with a day/night pattern. Our aims were to compare day/night patterns in seizure frequency among patients with different epileptogenic regions. METHODS: We analyzed video-EEG recordings in 15 patients with temporal lobe (TLE) and 11 with extratemporal lobe epilepsy (XTLE). Each seizure was classified according to subject group (TLE vs XTLE), sleep/wake state, and time of day of seizure occurrence (grouped into 6 x 4-hour "bins"). RESULTS: Of 90 seizures, 41 occurred in TLE and 49 in XTLE patients. There were day/night patterns of seizure occurrence in each group, with differences in the patterns between groups. In TLE, 50% of seizures occurred between the hours of 15:00 and 19:00 (17% would be expected by chance in each 4-hour "bin": F=3.59, P<0.006). In XTLE, there was a peak between 19:00 and 23:00 (47%: F=4.72, P<0.0018). The effect of time on seizures was least pronounced in the XTLE patients who had more than one epileptogenic region. The proportion of seizures occurring from sleep was significantly less in TLE (19%) than in XTLE patients (41%) [P<0.04, Fisher's exact test]. CONCLUSIONS: There are clear day/night patterns of seizure occurrence in epilepsy, with differences in the patterns between TLE and XTLE. There is an additional interaction with sleep/wake state, with relatively few seizures occurring from sleep in TLE compared with XTLE. Thus, it appears that both sleep/wake state and day/night or circadian rhythms may affect seizure proclivity, with different effects depending on the location of the epileptogenic region.     

Propagation of focal motor seizures in the pubescent monkey

The rate of local cerebral glucose utilization was determined for quantification of energy metabolism in macrostructures of the sensorimotor system during propagation of focal motor seizures in 24-month-old monkeys. The rate was measured in 4 control animals and in 4 monkeys each with seizures limited to the contralateral face, seizures of the contralateral face and upper extremity, and bilateral expression of seizures. Glucose utilization increased significantly, primarily unilaterally, with propagation. The increase was greatest in the sensory and motor cerebral cortices, putamen, and globus pallidus, was somewhat less in sensory and motor thalamic relay nuclei, and was least in the cerebellar cortex.     

Short-term neurodevelopmental outcomes of focal febrile seizures

ObjectiveThe effect of complex febrile seizures (FS), specifically focal FS, on long-term neurodevelopmental outcome is not well known. The aim of this study was to assess the association between complex FS and neurodevelopmental outcome.MethodsA single-center, retrospective, cohort study was performed. The study included 282 children aged 6–60 months who experienced FS. Of these, 61 (22%) experienced recurrent FS, 33 (12%) prolonged FS, and 17 (6%) focal FS. The effect of these complex FS on subsequent need for special neurodevelopmental support was investigated. The neurodevelopmental status after FS was evaluated by a questionnaire.ResultsDuring a median follow-up period of 3 years post FS, 12 children (4.3%) required special neurodevelopmental support. Univariate analysis demonstrated a significant association between focal FS and the need for subsequent special neurodevelopmental support, as well as a correlation between prolonged FS and pre-existing neurodevelopmental abnormality. Multiple logistic regression analysis demonstrated that focal FS (odds ratio [OR]: 12.27; 95% confidence interval [CI]: 2.11–71.22) and pre-existing neurodevelopmental abnormality (OR: 262; 95% CI: 17–3944) were significantly associated with the need for subsequent special support.ConclusionAn association was found between focal FS and subsequent neurodevelopmental impairment; therefore, close follow-up with particular attention to neurodevelopmental status is required for children who experience focal FS.     

Carbamazepine, clonazepam and focal reflex proprioceptive seizures

We studied a 34-year-old man with focal tonic-clonic seizures sometimes elicited by some active postures of the right hand and evolving at times to secondary generalization. Treatment with carbamazepine (CBZ) in combination with parenteral diazepam induced both a dramatic increase of focal reflex proprioceptive seizures and choreoathetoid dyskinesias in the affected hand. CBZ was withdrawn and clonazepam (CZP) given 2 mg daily, with complete relief of seizures and choreoathetoid dyskinesias. CZP had a suppressive effect on seizures for over 15 years, without development of tolerance.     

Independent component analysis in the study of focal seizures.

Independent component analysis (ICA) is a novel technique that can separate statistically independent elements from complex signals. It has demonstrated its utility in separating artifacts and analyzing interictal discharges in EEG. ICA has been used recently in ictal recordings, showing the possibility of isolating the ictal activity. The goal of our study was to analyze focal seizures with ICA, decomposing the elements of the seizures to understand their genesis and propagation, and to differentiate between various types of focal seizures. We studied 26 focal seizures of temporal, frontal, or parietal origin. Only seizures with suspected focal onset were included in the study. The EEG recordings were acquired by using standard video-EEG equipment, with scalp electrodes. All the off-line analysis was carried out on a PC by means of specific software developed in the Matlab environment. ICA components were calculated with the use of the JADE (Joint Approximate Diagonalization of Eigen-matrices) algorithm. The decomposition of the seizures varied according to the EEG seizure pattern. In the seizures with focal rhythmic theta slow or sharp waves, the rhythmic activity was separated into one to five components, having an initial component with a clear concordance with the focus, whereas the others had an onset a few milliseconds later and corresponded to neighboring areas. In the 6 frontal seizures with regional rhythmic low voltage fast activity, 4 to 10 components were found, practically with a simultaneous timing, having a frontal distribution. In the three frontal seizures with a diffuse attenuation of the EEG signal, it was not possible to differentiate components of cerebral origin from the components of muscle artifact. ICA is an interesting tool to study the nature of focal seizures. The results depend on the EEG pattern. In the seizures with a clear EEG focal pattern, ICA may be useful to separate components of the ictal onset from the propagated activity.     

Efficacy of the ketogenic diet in focal versus generalized seizures

Most reports of the ketogenic diet have focused on its efficacy for generalized seizures. Few data are available regarding its effect on focal seizures. We retrospectively studied patients (mean = 7.5 years of age) with medically intractable epilepsy treated by the ketogenic diet. The predominant seizure types in each patient were classified as generalized (100 patients) or focal (34 patients) based on ictal electroencephalograms (EEGs) or seizure semiology and interictal EEG. A seizure reduction of more than 50% compared with baseline was seen in nine patients (27%) with focal seizures and 46 patients (46%) with generalized seizures at 3 months, in 10 patients (30%) with focal seizures and 46 patients (46%) with generalized seizures at 6 months, and in eight patients (24%) with focal seizures and 42 patients (42%) with generalized seizures at 12 months. Differences were not significant. Outcome tended to be better in patients younger than 12 years of age compared with the older age group, but the difference was significant at 6 months only. Our results suggest that some patients with intractable focal epilepsy may respond favorably to the ketogenic diet and that this option should be considered if epilepsy surgery is not possible.     

Effectiveness of muscimol-containing microparticles against pilocarpine-induced focal seizures

PURPOSE: To investigate the efficacy of in situ lipid-protein-sugar particles (LPSPs) in mitigating the epileptogenic and histologic effects of intrahippocampal pilocarpine in rats. METHODS: LPSPs with and without muscimol were produced by spray-drying, sized by Coulter counter, and muscimol content determined by high-pressure liquid chromatography (HLPC). Particles, free muscimol or saline, were injected into the hippocampi of Sprague-Dawley rats before 40 mM pilocarpine, and seizure activity was scored. The trajectories of behavioral scores between groups were compared with two-way repeated measures analysis of variance. Animals were killed after 2 weeks. Brain sections were stained (Timm and thionin) and scored. RESULTS: LPSPs were 4 to 5 microm in diameter, and contained 0 or 2% (wt/wt) muscimol. In vitro, muscimol was released over a 5-day period. Intrahippocampal injections of normal saline and blank LPSPs did not deter seizure activity from pilocarpine. The rise of the trajectory in behavior scores in animals given LPSPs containing 5 microg muscimol was significantly slower than in those receiving saline, blank particles, or 5 microg of unencapsulated muscimol. There was less apparent neuronal injury and CA3 and supragranular mossy fiber sprouting in hippocampi of animals receiving muscimol-containing particles than in animals that did not receive muscimol. Hippocampi of animals that received 5 microg of encapsulated muscimol showed less supragranular sprouting than did those receiving 5 microg of unencapsulated muscimol, but showed no difference in cell loss or CA3 sprouting. CONCLUSIONS: Focally delivered biodegradable microparticles loaded with muscimol are effective in reducing seizure activity from pilocarpine in animals and mitigate the histologic effects.